1. Field of the Invention
The invention is directed to the preparation of certain chemotherapeutic materials useful in the treatment of viral infections and tumors associated with viruses. More specifically, the invention is directed to the preparation of adenosine deaminase resistant antiviral purine nucleosides.
2. Description of the Prior Art
The antiviral nucleoside 9-.beta.-D-arabinofuranosyladenine (ara-A) was first synthesized in a program designed to produce anticancer agents. Recent interest in the promising antiviral activity of ara-A has been extensively reviewed. Broad spectrum activity of ara-A against DNA viruses and significant therapeutic activity of ara-A against experimental herpes simplex keratitis and herpes simplex and vaccinial encephalitis has been reported. A major liability in the use of ara-A lies in the fact that the nucleoside is rapidly deaminated by a commonly occurring enzyme, adenosine deaminase. Deamination of ara-A renders it much less effective and high doses of the drug are required at frequent intervals. Although the deamination product, 9-.beta.-D-arabinofuranosyl-hypoxanthine (ara-H), is also active against DNA viruses, it is considerably less active than ara-A. A major effort to circumvent the deamination problem employs the use of ara-A in combination with adenosine deaminase inhibitors such as deoxycoformycin or erythro-9-(2-hydroxy-3-nonyl)adenine. This approach presents a problem in that the Food and Drug Administration is reluctant to approve and physicians are reluctant to prescribe a compound that inhibits an enzyme with a normal body function. A more desirable approach to the development of a more active antiviral or antitumor agent, followed by applicant, involves the use of a deamination resistant ara-A derivative. The carbocyclic ara-A analogs described herein circumvent the major disadvantage of ara-A because they are completely resistant to degradation by adenosine deaminase.